Background: Succinate, although most famous for its role in the Krebs cycle, can be released extracellularly as a signal of cellular distress, particularly in situations of metabolic stress and inflammation. Solitary chemosensory cells (SCCs) express SUCNR1, the succinate receptor, and modulate type 2 inflammatory responses in helminth and protozoal infections in the small intestine. SCCs are the dominant epithelial source of interleukin-25, as well as an important source of cysteinyl leukotrienes in the airway, and have been implicated as upstream agents in type 2 inflammation in chronic rhinosinusitis (CRS) and asthma.
Methods: In this study, we used scRNAseq analysis, live cell imaging of intracellular calcium from primary sinonasal air-liquid interface (ALI) cultures from 1 donor, and measure antimicrobial peptide release from 5 donors to demonstrate preliminary evidence suggesting that succinate can act as a stimulant of SCCs in the human sinonasal epithelium.
Results: Results from scRNAseq analysis show that approximately 10% of the SCC/ionocyte cluster of cells expressed SUCNR1 as well as a small population of immune cells. Using live cell imaging of intracellular calcium, we also demonstrate that clusters of cells on primary sinonasal ALI cultures initiated calcium-mediated signaling in response to succinate stimulation. Furthermore, we present evidence that primary sinonasal ALI cultures treated with succinate had increased levels of apical beta-defensin 2, an antimicrobial peptide, compared to treatment with a control solution.
Conclusion: Overall, these findings demonstrate the need for further investigation into the activation of the sinonasal epithelium by succinate in the pathogenesis of CRS.
Keywords: asthma; brush cell; chronic rhinosinusitis; nasal polyps; solitary chemosensory cell; succinate; tuft cell.
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